1. Field of the Invention
The present invention relates to a process for the production of cis-(.+-.)-3,4-dihydro-N,N,2-trimethyl-2H-1-benzopyran-3-amine(I) and to certain intermediates used in the production thereof.
2. Description of the Prior Art
As disclosed by Lockhart, I. M., in U.S. Pat. No. 3,607,866, N,N,2-trimethyl-3-chromanamine, .alpha.-isomer (which is the cis-(.+-.)-3,4-dihydro-N,N,2-trimethyl-2H-1-benzopyran-3-amine designated compound I in the subject invention) exhibits antidepressant activity. According to U.S. Pat. No. 3,607,866, N,N,2-trimethyl-3-chromanamine,.alpha.-isomer, and its acid addition salts may be produced by reacting 2-methyl-3-nitro-2H-1-benzopyran with lithium hydride and hydrolyzing the product to obtain 2-methyl-3-chromanamine,.alpha.-isomer and .beta.-isomer from which the .alpha.-isomer is subsequently separated by a precipitation and recrystallization process. The .alpha.-isomer is then methylated to obtain the desired N,N,2-trimethyl-3-chromanamine.
In the U.S. Pat. No. 3,629,289, a related Lockhart patent, the .alpha.-isomer of 2-methyl-3-chromanamine intermediate and the process for its preparation are more fully described.
Bachman, et al. in J. Am. Chem. Soc. 70: 599-601 (Feb. 1948) disclose the preparation of 2-methyl-3-aminochroman by hydrogenation of 2-methyl-3-nitro-1,2-benzopyran using a Raney nickel catalyst.
In aforementioned U.S. Pat. No. 3,607,866 and in U.S. Pat. No. 3,629,289, the distinction between the .alpha.- and .beta.-isomeric forms of the compounds prepared is discussed, particularly with respect to the physiochemical and pharmacological properties.
Lovgren, K., et al., in Acta. Pharm. Suecica 14:21-29 (1977) disclose the preparation of certain cis and trans 3-hydroxy-4-isopropylaminochromans starting with 6-methoxy-2H-chromen. Lovgren, et al. recognize that two completely different syntheses are required to obtain the cis and trans isomeric configurations. Intermediates formed during the synthesis of the trans isomers include trans-3,4-dibromo-6-methoxychroman and trans-3-bromo-4-hydroxy-6-methoxychroman. However, since none of the Lovgren compounds have a 2-methyl substituent, this reference is concerned only with isomerism at the 3,4-position of the chroman ring. In the instant invention, the 2-methyl substituent presents additional isomeric possibilities which are not considered in the Lovgren, et al. reference.
The preparation, isomeric configuration and pharmacological properties of related aminochroman derivatives are discussed in the following references: Huckle, et al., J. Med. Chem.12:277-279 (1969); Lockhart, et al., J. Med. Chem. 15: No. 8, 863-865 (1972); Sarda, et al., C.R. Acad. Sc. Paris 279: 281-4 (Aug. 12, 1974); Sarda, et al., Eur. J. Med. Chem. 11: No. 3,251-257 (May-June, 1976); and Sarda, et al., Eur. J. Med. Chem. 11: No. 3,257-262 (May-June, 1976).
In Japanese 52-083-829 (Takeda Chemical Industries) ring opening of an azirine derivative is achieved by hydrolysis: 5,6-dihydroxy-1,1.alpha.,2,3,4,8b-hexahydro-benzo[3,4]cyclohepta[1,2-b]azi rine is hydrolyzed to form 1,2,5-trihydroxy-6-isopropylamino-6,7,8,9-tetrahydro-5H-benzocycloheptane hydrobomide, a useful remedy for asthma. The azirine derivative of the sixth reaction step of the instant invention involves a different ring system and ring opening is achieved by means of catalytic hydrogenation.